These three things is the autistic phenotype.
You name me. You go find me one autistic phenotype
that does not have problems with the central
nervous system, the peripheral nervous system,
and the enteric nervous system. You can't. You
can't find it. There we go. Okay, this one's
going to be dense. This one's going to be fun.
This is neural relation. We're going to cover
specifically two episodes we did on We're just
writing down here. 56 is called Autism Neuralation
and Autism Neuralation and Embryogenesis. Episode
57. Neuralation. Neuroepithelial cells and mesencephalon.
Which is a type of neuroepithelial cell. Oh,
I'm close. We'll make it. We're gonna make this.
Tryptophan. These two kind of will branch off
out of these two. Nicely. You'll see. Hopefully.
And they're way back. Way back in the old episode.
We really went into kind of embryogenesis to
kind of perinatal. Just after birth. I think.
Maybe up to two years. I can't remember. I can't
remember actually. But we spent a lot of time
UC San Diego. Every tower they spend a lot of
time on in this little epoch. It's great stuff.
They have great data That episode really went
into kind of artificial light we're gonna get
there though, so We're kind of gonna be talking
about these two episodes mostly so I just spent
a lot of time writing those episodes out I probably
shouldn't have done that just stick to this kind
of like the objective of the information. So
we're going to talk about Neuralation and Embryogenesis,
and this is the Neuroplate, okay? So this comes
on board around day 21, 23 or so. This is what
we are to begin with. The glare is okay, I think.
Neuroplate. So we got the Epidermis in the blue.
neuroectoderm is here in the middle and then
the little green is called a border and then
this thing folds see this this will fold in and
the neuroectoderm will come down and this is
um we have different types of derm now ectoderm
is at the very edges the mesoderm is the next
layer kind of in and the endoderm is the center
of this fold And this is where skin and nervous
systems will begin. Skin and nervous systems
are like that. And then we have the tube, because
we're folding into a tube. And we have the epidermis.
It's growing larger, okay. It started here. We
have the epidermis on top. And then the green
are neurocrest cells. And then we have the tube,
which is right here, the neuroectoderm. So when
Jack Crew says things like the skin and the oral,
oral tissues and so forth, and the central nervous
system are combined. They're like that. So this
tube will go on to develop the brain and spine,
the central nervous system. These neurocrest
cells, they're just kind of drawn as circles.
This is where already on board melanocytes, melanocytes
are being created. Remember because of the skin
and then the adrenals our adrenals we think of
things like adrenaline and cortisol and so forth
and then face and bone and cartridge and then
here the peripheral and enteric nervous systems
are beginning so this is more central nervous
system and this is more peripheral and enteric
nervous system okay now there's some key components
here that are very um worth mentioning and we've
done we've covered these um so just kind of recapping
these shh what is this we have this and it's
huge in development sonic hedgehog sonic hedgehog
this is involved in proliferation So we're going
to be making cells here, right? We make a lot
of cells here. We proliferate cells. Cells divide.
It's kind of just the process. Progenitor cells
is big with the sonic hedgehog. Progenitor cells
and cell growth. And they control, sonic hedgehog
will also control cell survival. Sonic hedgehog
is involved with motor neurons and Interneurons.
What are those? We could simplify neurons in
the central nervous system as sensory neurons,
interneurons, and motor neurons. If we want to
really have like a simplistic view of things.
Sensory neurons, they're involved with sensory
input. Interneurons are things that are connecting
regions. Things like excitation inhibition. And
then the motor neurons are responsible for Things
I'm doing right now. Just moving. I'm constantly
moving. EI is a big one here. From here. Okay.
Now, if you look at data, research data, and
you can find like mice and rat models of autism.
If you knock out, it will look like this. Sonic
Hedgehog knock out. The mouse or rat will not
develop the thalymic reticular nucleus. This
part comes from the ventral thalamus. Okay, so
if you knock out this in a mouse or rat model,
they will not develop this or that. So this must
be a region of interest for us because of this.
Remember the par of albium interneuron specifically.
And then this. We've covered that in an episode
about inhibition. Because that's a sensory gate.
It protects the thalamus. You don't want the
thalamus to be over your hand. Insane. Okay,
okay. We're getting there. Shoot, we're already
nine minutes in. God bless it. Next one is P10.
Phosphor... Phos... Four... Case. No, that's
not right. Phosphortensin. For sure it's tensin,
but I don't know how to spell it. Let me check
my notes. That's it? Insane. ACE. Anytime you
see ACE, it's an enzyme. So this is an enzyme.
P10. It's huge. This is going to be huge. This
is a lipid and protein phosphor. I can't spell
that. I can't. Lipid and protein phosphors. All
of our membranes except for the inner mitochondrial
membrane, or lipid. Lipid phosphorus. Every cell
membrane. This is huge. This is also involved
with regulating neurolation here. In a large
part. Okay. There's a pathway P, let me see.
Yeah. There's a lot of PIP. You'll see a lot
of PIP involved, like two, three, and so forth,
with this. But let's not get distracted here.
AKT and mTOR mammalian target of rapamycin okay
this is huge in this this process okay especially
the neural plate okay this is going to be such
a region of interest this is also involved with
and because it's lipid and phosphorus microtubules
we have an episode on that I wrote it out and
mitochondrial biogenesis okay this there's a
study recently eric et al in 2021 or 2022 i can't
remember i can't remember but it's in cell press
cell press is a fantastic journal uh it's actually
movie cell reports i can see the graphical abstraction
so so press Journals have this great graphical
abstraction and then like three or four key highlights.
They're it's very good stuff. Okay, so They study
that a loss of p10 and then mtor Complex one.
You'll see it as m -t -o -r -c -1 I forget what
they did. I forget if they rescued the lack of
p10 by targeting complex one or what I don't
I don't know. But this is a good region of interest
here for us. This regulates cell growth, proliferation,
survival, and differentiation as well. And the
proliferation here into differentiation into
a mature cell. P10 is also involved in things
like cancer growth and things like that. Okay.
Now we're getting somewhere I think. Because
we got to get to the mesencephalon. We got to
get to the mesencephalon big time. And also,
and we won't spend much time on this one. B9,
okay. Methylene tetrahydrofolate reductase. No,
what did I say? Methylene tetrahydrofolate reductase.
Methylene. This is the motherfucker gene. And
this is B9. This is leukovorin. Okay, I'm not
going to sit here and explain this because you
can go see Richard Fry and Nicole Rincon. Probably
the best in the world best in the world former
guest on the podcast best in the world on this
this phalamic acid and Leukovorin, okay, this
is building block though for Protein synthesis
and so forth and DNA methylation. This is a big
thing that the DNA methylation remember Richard
Frye we talked about how Leukovorin is helping
Possibly the distal connections like from the
superior colliculus to the frontal eye fields
is a very distal connection or the superior temporal
gyrus, sometimes verneckis and so forth, to Broca
for the speech and language. This is going to
be a big thing here. It's also involved with
methionine. It provides SAM, the donor or cofactor.
to methionine methionine and tryptophan which
we're going to talk about now they are fantastic
amino acids because they only have one codon
tryptophan and methionine are so special you
know this this is an aromatic amino acid this
means it needs uv light aromatics are uv light
antennas essentially they have benzene rings
and um pi electrons and things and so forth which
helps it synthesize. Tryptophan is like around
277, 283 type of peak absorption, which is right
on the line of UVB, UVB sourced at 280. But this
is huge because maternal peripheral tryptophan
equals brain. Tryptophan serotonin. The mother
peripheral tryptophan is how the fetal forebrain
gets tryptophan and serotonin nobody does anything
with this stuff though i'm telling you nobody
nobody cares nobody does anything with this stuff
this is involved with those sensory maps serotonin
has massive roles outside of mood outside of
it's so unbelievable to me serotonin has hidden
rows, okay, with receptors and cell differentiation
and proliferation with initially overgrowth of
neurorites. Neurorites are axons and dendrites.
How much information do we need about autistic
phenotype having abnormal axon and dendrite?
I don't know. I don't know. Especially in the
central nervous system and the peripheral nervous
system. Serotonin. Serotonin. It's unbelievable
to me. The mother's tryptophan levels, remember,
remember, tryptophan being that aromatic amino
acid, if it's under hypoxia, okay, so you have
tryptophan and that synthesizes serotonin and
then some melatonin, ugh, that's melatonin, okay?
Oxygen levels will move this this way. Depending
on your oxygen levels and ROS things like that.
So it depends on the oxygen and So forth will
depend on how the tryptophan is being synthesized
or not being synthesized Nobody cares. I don't
think I don't know. I don't know what's I don't
I don't know. I don't know what's Why things
like this is this? so foreign in autism research
Okay, anyways, so once we get here once we get
this we're going to spend more most time here
for the central nervous system so there's four
four cell types that will come on board neuro
epithelial cells which will become four cells
as well and then let's see the the neural crest
cells will begin to do different things um the
ectoderm okay so kind of it's just expanding
out here and then mesoderm okay it's just you
know we're we're this and then well maybe like
that and then we fold and then this another layer
comes on and then we're just eventually becoming
you know we're just expanding it's almost like
a finger looks better because we're about to
draw this out right now We're about to draw it
out. We're just gonna get rid of this. Because
we gotta get to the mesencephalon. We gotta get
to the mesencephalon. And these epicy of cells.
So we're just gonna go here, okay? Because we're
developing the brain here. Brain and spine, central
nervous system, okay? So I need different colors
here, I think. I think that's what we'll do.
Red's gonna be mesencephalon, I think. We'll
have to do red for mesencephalon. Okay, so we
have the pro -encephalon. Remember, there's four
different cell types. Pro -encephalon, mes -encephalon,
and then we'll go green. We'll go green for the
rom -encephalon because it's a lot of going,
a lot of reflexes. And then the fourth one, to
be honest. It's, it's making the spine. It's
making the spine. So right after, right after
that fold and tube and the epidermis coming on
board, we kind of start looking like this. Okay.
This is what we're kind of just looking like
here. Okay. This is pro here, mesencephalon here,
romencephalon here, spine. All right. So these
will begin to subdivide. So the proencephalon,
The forebrain goes into, I hope you guys can
see this, telencephalon and diencephalon. Okay,
so essentially this one is the cortex, this one's
the subcortical areas, okay? And then we'll start
to look like this. It's almost like a heart.
Maybe I'll draw it keeping with this theme, okay?
So we'll start going like this. Okay, it's getting
bigger, is what we're doing. This one, if you
know, if you follow along with the podcast and
me ranting about this all the time, nothing.
This one will make the MET encephalon and the
MY encephalon. So this will become the cerebellum
and pons. And this one is the medulla. Okay,
so... Let's see, we'll start looking like this.
Okay, that's good. That's good there. So this
is the pronencephalon. Okay, it's just The big
the big head that's it's the majority of our
brain is right here This is the smallest part
and then this is the bottom of the brain stem
or most of the brain stem and then the spine
Okay, so let's draw this out as the brain All
right so the proencephalon so It might be easier
to go bottom up. I'm just going to go bottom
up So we have the brain stem here the start of
the brain stem the medulla Okay, this is the
medulla and then let's see so this this is the
myencephalon Okay, and then the metencephalon
the pons is a little football oval shape that
sticks out in the front side of the the brain
stem. And then we also have deep inside here.
It's kind of covered. Sometimes you'll see it
covered with things like the occipital, temporal.
Sometimes you won't. It just depends. But I'm
just going to cover it. And then the mesencephalon.
Okay. I got to go up higher because the mesencephalon
is not very big. The mesencephalon will be like
that. And then I need blue. I need blue here.
Okay. I gotta finish this out. We might just
cover it though. So we have that like the occipital
lobe and the parietal lobe. That sensory motor
area. The frontal eye fields will be here. And
then we'll get into the prefrontal cortex. Then
this kind of, you know, it just kind of comes
in. and then the temporal lobe kind of do this
thing right here okay then like your eyes will
be here retina your eye things like that so this
is responsible for all of this this is only responsible
for here and then this is key areas a lot of
autonomic functioning right here all right so
let's talk about The big thing here. Oh, this
is way too long. I gotta clean this stuff up.
Let's just go ahead and draw this out. Because
this is the whole part. Everything about autism
might be able to be explained right here. Everything.
During this timeline, too. Okay? We talked about
how the central nervous system, the peripheral
nervous system, things like the oral microbiome,
The first time Richard Fry was on the episode,
he mentioned like a size of a one of the teeth.
Oh, goodness. My teeth, my teeth thing. I don't.
I'm not good with molars. One of the molars,
the size of a molar will predict autism. Richard
Fry told us that. And AJ Drexel was on that study.
Kristen Lyaw was on that study. And at what?
That's what connected me to Kristen Liao, who
was on in December. Kristen Liao, Modifiable
Risk Factors with Autism, received one of the
new NIH grants for investigating autism. Okay,
let's get into this. I'm going to draw what you
might think is a butterfly. Okay. I'm going to
try to do this good, too, because this is going
to be hard. No, that's not so bad. We're looking
straight on, straight down. Into the mesencephalon
here. Okay, so we removed the whole top part
of the head and we're just looking straight down
into it Alright, so we're gonna have different
regions here. Okay, I should have used different
colors That's fine. This dark spot here is the
substantia nigra substantia nigra which translates
into black substance or a substantially black
black substance okay this is um the mesencephalon
can be divided into three main parts okay this
is like a um pre yeah not pre it's like uh i
don't know cerebral something i have no idea
what this area is to be honest and it's right
here the front part okay and then we have might
as well make it red red nucleus It's involved
with motor movements, different types of motor
movements. Okay, we'll go blue for a lot more
of this stuff. Here, medial geniculate nucleus.
Okay, this is actually part of the thalamus.
This is where auditory goes as a relay station
for the thalamus. because this brain stem coming
up the brain stem is going to be heavily involved
with um um auditory sensory and we're going to
get to the sensory part okay i'm just kind of
just drawing this stuff out now i want want brown
for para -aqueductal gray okay let's see this
part is going to be huge because we talked about
this part quite in detail superior colliculus
eye movements eye movements will go right here
Once it hits the lateral geniculate these will
send some fibers down to here and this will go
back up and recruit the frontal eye fields here
and then just be like a distal connection and
it helps with modulating our eye gaze and eye
contact and things like that. So this is also
receiving inputs just like visual cortex one.
So I think it's probably like identical timing
after the lateral geniculate. Okay, so then there's
also some cranial nerves. Okay, there's some
cranial nerves. This, this is ocular motor, more,
more eye movements. Look over here. A thing called
Edinger Westfall. This is This is kind of some
eye movements too, but there's some, there's
some choline involved here. This is, this has
like two parts to it. Okay. One is the choline
and it will send information down to ganglia
ganglion fibers, but this has indirect, um, influence
with, um, we're almost trying to say pupil constriction
because I was thinking about the light reflex,
pupillary light reflex, which is a hidden danger.
It's a very hidden danger with LEDs and blue
light. I think this is going to be hitting hard
because if you think about it too, it's sending
ganglionic fibers down the spine which is full
of ganglionic fibers and our eyes with the constriction
and dilation and so forth with these light flicker
that we cannot see but it's happening. okay and
then ocular motor so there's massive amounts
of um eyes going on here and there's some cranial
nerves three cranial nerves three and four are
here um that hole right there i think this is
where cerebral spinal fluid comes up from the
spine and then into the brain because right on
top of the The mesencephalon is this thing. That's
awful. It looks like a talon. And this area right
here is full of water. There's not a lot of blood
-brain barrier here. Looks like a talon. And
all of these surfaces are surrounding this. When
you see things like this in the middle of the
brain, Like the cadet nucleus has a long shell.
It's like right here. You can see these things.
There's like a fornax that's extending off from
the amygdala. It just depends on how lateral
you are. But you can see it like this. It's a
paraventricular area right here. Lots of water.
Lots of water. So this is huge because the mesencephalon
here I'm just gonna get rid of this stuff because
the mesencephalon has three main roles Motor
movement which is the red nucleus, but mainly
here because this is broken down into two parts
pars Compacta which is both dopamine. This is
huge. This is The basal ganglia okay and Parkinson's
because we're going to I'm going to draw something
out about Parkinson's real fast here in here
in a second um and then the other part of the
substantia nigra is pars reticulata that reminds
me too the reticular formation is very much involved
here the reticular formation is if we just draw
the brain stem again at the start of the cerebellum
and then you know the mesencephalon is here What
was I talking about? I forget what I was talking
about. But the pars reticulata is GABA, okay?
And this is synonymous with Vomus Pallidus internal.
The reticulata and Vomus Pallidus internal are
kind of like output areas of the basal ganglia,
which is regulating movement, correct and indirect
pathway. We'll do whiteboard episodes on that
because it's... heavily involved in parkinson's
man so bad what was i doing here i don't remember
but if you can oh never mind sensory integration
okay multiple forms of sensory you have you have
the cranial nerves here right you have um the
superior colliculus which is receiving Eyes,
eye movements. You hear a sound over here and
you're just, you know, it's just reflexive. This
is a very powerful area. And like barn owls,
it's called optic tectum. Great research on that
with Eric Knudsen. Knudsen from Stanford. Go
see his stuff, man. He has great papers. But
this also incorporates sound, right? Because
if you hear a sound to your left and you automatically
look, you can pick up that target pretty accurately.
That's so reflexive. And then overall, this little
area here is orienting attention. But what kind
of attention? To the outside world. All of this
stuff is receiving information fast from the
outside world and then kind of recruiting distal
areas, right? Substantial Niagara with the basal
ganglia, eye movements, hearing. PAG is big with
pain perception and just kind of, you've probably
heard, I know you've heard of fight. flight or
freeze. When we freeze, the PAG receives information
from areas like the hypothalamus and probably
the habinula and the amygdala. The para -aqueductal
gray. When we freeze, remember there's a lot
of ganglionic fibers running down the spine from
this area. This thing is shut off. This thing
shuts the spine off and it just shuts your motor
movements off. It's so powerful. This area right
here is so powerful. But this right here, these
three things is the Autistic Phenotype. You name
me, you go find me one Autistic Phenotype that
does not have problems with the Central Nervous
System, the Peripheral Nervous System, and the
Enteric Nervous System. You can't. You can't
find it. This is also involved because I mentioned
the reticular formation with sleep, the mesencephalon,
and even this brainstem. So here we go. The reticular
formation is just a collection of areas here
within the brainstem, just like different areas.
And it has ascending and descending fibers. The
reticular formation Big with this of course it
is so let's talk about that Picture of the Parkinson's
because you can look this up. This is this isn't
hard to find Okay, so I'll do brown because it's
supposed to be like Tissue, okay, so let's draw
this out real fast just real loosely. It doesn't
matter How good it is or accurate? Okay, so we
have this cerebral uncle thing then I want to
draw another one okay and then the substantial
nigra here right here this is Parkinson's it's
black remember because it has neuromelanin in
it it's loaded with neuromelanin these areas
right here because it's full of water melanin
and water is our energy source this is biological
energy the blood -brain barrier here is very
weak because there's so much water. There's so
much electrical power coming through here. So
with healthy people, the substantia nigra is
dark because of that neuromelanin. With Parkinson's,
you can barely see tissue. You can barely see
it with Parkinson's because their neuromelanin
is gone. And this and this and this right here.
It's controlling movements. You think about the
autistic phenotype and stereotyping. Stemming.
We'll do some more stuff on the basal ganglia.
This little epoch of time is so underrated. I
feel like so much of what we talk about is just
so underrated. Is that because autism research
just finds things and nothing is followed up?
But, mesencephalon. This is why I'm so fascinated
with the mesencephalon.